ABSTRACT The Genomic Editing and Screening (GES) Core was established in 2012 with institutional funds. Initially, it provided cutting-edge RNA interference (RNAi) gene target knockdown technologies toward the discovery of novel cancer targets and elucidation of complex aberrant intracellular pathways. A central feature is the use of third generation Pol II-driven, enhanced Mir30-based shRNA for high functional protein knockdown efficiency at single-copy integration, using a diverse panel of packaged retro-and lentiviral plasmid backbones for effective delivery. Establishment of this platform subsequently allowed for the rollout in 2014 of CRISPR-Cas9 sgRNA single-gene and full-genome knockout technologies via pooled libraries. Realization that many cell types are easily transfectable and that discrete intracellular events such as activation, translocation, and cell- to-cell communication can be quantified using high-speed automated fluorescence microscopy, the Core initiated high content imaging and analysis (HCA) for arrayed siRNA experimentation. A natural extension of this 96/384 well plate format was then evolved into a workstation-based small molecule compound screening program, allowing investigators to effectively phenocopy newly-identified targets using chemical biology approaches. The most promising of these compounds are then matriculated into the Early Therapeutics Center (ETC) and Tri-Institutional Therapeutic Drug Initiative (TRI-I TDI). Overall, this multi-modal Core enables mechanism-based science through target identification and drug screening, offering custom reagents and services to a growing number of the Center?s members.